Intellectual disability, autosomal recessive 42

Summary

Intellectual disability, autosomal recessive 42 (MONDO:0014348) is a disease caused by PGAP1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: PGAP1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 303

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 42
Mondo ID	MONDO:0014348
OMIM	615802
UMLS	C4014343
MedGen	862780
GARD	0022564
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in PGAP1 · intellectual disability, autosomal recessive 42 · intellectual disability, autosomal recessive type 42 · mental retardation, autosomal recessive 42 · mental retardation, autosomal recessive type 42 · MRT42 · neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities · PGAP1 autosomal recessive non-syndromic intellectual disability

Data availability: 303 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 42

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

303 retrieved; paginated sample, class counts are floors:

116 likely benign, 109 uncertain significance, 20 benign, 19 pathogenic, 17 conflicting classifications of pathogenicity, 10 likely pathogenic, 7 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101081	NM_024989.4(PGAP1):c.1952+1G>T	PGAP1	Pathogenic	no assertion criteria provided
1032203	NM_024989.4(PGAP1):c.1663C>T (p.Gln555Ter)	PGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064599	NM_024989.4(PGAP1):c.1221-3A>G	PGAP1	Pathogenic	criteria provided, single submitter
1072363	NM_024989.4(PGAP1):c.1952+1G>C	PGAP1	Pathogenic	criteria provided, single submitter
132084	NM_024989.4(PGAP1):c.586CTT[1] (p.Leu197del)	PGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1980388	NM_024989.4(PGAP1):c.20del (p.Asn7fs)	PGAP1	Pathogenic	criteria provided, single submitter
2023072	NM_024989.4(PGAP1):c.275del (p.Pro92fs)	PGAP1	Pathogenic	criteria provided, single submitter
222977	NM_024989.4(PGAP1):c.1572T>A (p.Tyr524Ter)	PGAP1	Pathogenic	criteria provided, single submitter
222978	NM_024989.4(PGAP1):c.1396C>T (p.Gln466Ter)	PGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222979	NM_024989.4(PGAP1):c.274_276del (p.Pro92del)	PGAP1	Pathogenic	criteria provided, single submitter
222980	NM_024989.4(PGAP1):c.921_925del (p.Lys308fs)	PGAP1	Pathogenic	criteria provided, single submitter
222981	NM_024989.4(PGAP1):c.1090-2A>G	PGAP1	Pathogenic	no assertion criteria provided
2770871	NM_024989.4(PGAP1):c.1867del (p.Cys623fs)	PGAP1	Pathogenic	criteria provided, single submitter
3233391	NM_024989.4(PGAP1):c.861-2A>G	PGAP1	Pathogenic	criteria provided, single submitter
3235692	NM_024989.4(PGAP1):c.1546_1549del (p.Val516fs)	PGAP1	Pathogenic	criteria provided, single submitter
4292408	NM_024989.4(PGAP1):c.1869C>A (p.Cys623Ter)	PGAP1	Pathogenic	criteria provided, single submitter
436299	NM_024989.4(PGAP1):c.927+1G>A	PGAP1	Pathogenic	criteria provided, single submitter
474988	NM_024989.4(PGAP1):c.1394_1397del (p.Ile465fs)	PGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
474992	NM_024989.4(PGAP1):c.427C>T (p.Gln143Ter)	PGAP1	Pathogenic	criteria provided, single submitter
503954	NM_024989.4(PGAP1):c.2357_2358insTA (p.Arg786fs)	PGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
801847	NM_024989.4(PGAP1):c.2274C>G (p.Tyr758Ter)	PGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915318	NM_024989.4(PGAP1):c.776T>G (p.Leu259Ter)	PGAP1	Pathogenic	criteria provided, single submitter
983046	NM_024989.4(PGAP1):c.2042del (p.Leu681fs)	PGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
983141	NM_024989.4(PGAP1):c.1501-2A>G	PGAP1	Pathogenic	criteria provided, single submitter
1477187	NM_024989.4(PGAP1):c.2286+1G>A	PGAP1	Likely pathogenic	criteria provided, single submitter
2502370	NM_024989.4(PGAP1):c.289del (p.Ser97fs)	PGAP1	Likely pathogenic	criteria provided, single submitter
2671723	NM_024989.4(PGAP1):c.2393C>G (p.Ser798Ter)	PGAP1	Likely pathogenic	criteria provided, single submitter
2687791	NM_024989.4(PGAP1):c.1272G>A (p.Lys424=)	PGAP1	Likely pathogenic	no assertion criteria provided
2703351	NM_024989.4(PGAP1):c.1351-2A>G	PGAP1	Likely pathogenic	criteria provided, single submitter
2746971	NM_024989.4(PGAP1):c.2287-1G>A	PGAP1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PGAP1	Strong	Autosomal recessive	intellectual disability, autosomal recessive 42	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PGAP1	Orphanet:401820	Autosomal recessive spastic paraplegia type 67
PGAP1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
GPI	Orphanet:712	Hemolytic anemia due to glucophosphate isomerase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PGAP1	HGNC:25712	ENSG00000197121	Q75T13	GPI inositol-deacylase	gencc,clinvar
GNPDA1	HGNC:4417	ENSG00000113552	P46926	Glucosamine-6-phosphate deaminase 1	clinvar
GPI	HGNC:4458	ENSG00000105220	P06744	Glucose-6-phosphate isomerase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PGAP1	GPI inositol-deacylase	GPI inositol-deacylase that catalyzes the remove of the acyl chain linked to the 2-OH position of inositol ring from the GPI-anchored protein (GPI-AP) in the endoplasmic reticulum.
GNPDA1	Glucosamine-6-phosphate deaminase 1	Catalyzes the reversible conversion of alpha-D-glucosamine 6-phosphate (GlcN-6P) into beta-D-fructose 6-phosphate (Fru-6P) and ammonium ion, a regulatory reaction step in de novo uridine diphosphate-N-acetyl-alpha-D-glucosamine (UDP-GlcNAc…
GPI	Glucose-6-phosphate isomerase	Isomerase that catalyzes the conversion of alpha-D-glucose-6-phosphate to beta-D-fructose-6-phosphate, the second step in glycolysis, and the reverse reaction in gluconeogenesis, within the cytoplasm.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PGAP1	Other/Unknown	no		PGAP1-ab_dom-like, AB_hydrolase_fold, PGAP1/BST1
GNPDA1	Enzyme (other)	yes	3.5.99.6	Glucosamine6P_isomerase, Glc/Gal-6P_isomerase, Glucosamine6P_isomerase_CS
GPI	Enzyme (other)	yes	5.3.1.9	G6P_Isomerase, Phosphoglucose_isomerase_CS, G6P_Isomerase_C

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
ganglionic eminence	1
upper leg skin	1
adult organism	1
nephron tubule	1
type B pancreatic cell	1
apex of heart	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PGAP1	271	ubiquitous	marker	endothelial cell, ganglionic eminence, upper leg skin
GNPDA1	298	ubiquitous	marker	type B pancreatic cell, nephron tubule, adult organism
GPI	286	ubiquitous	marker	apex of heart, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPI	4,709
GNPDA1	1,687
PGAP1	882

Intra-cohort edges

A	B	Sources
GNPDA1	GPI	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPI	P06744	13
GNPDA1	P46926	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP1	Q75T13	89.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycolysis	2	190.3×	2e-04	GNPDA1, GPI
Attachment of GPI anchor to uPAR	1	423.0×	0.006	PGAP1
Gluconeogenesis	1	146.4×	0.011	GPI
TP53 Regulates Metabolic Genes	1	43.3×	0.029	GPI
Neutrophil degranulation	1	7.7×	0.124	GPI

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
carbohydrate metabolic process	2	90.6×	0.006	GNPDA1, GPI
D-glucosamine catabolic process	1	1872.4×	0.007	GNPDA1
N-acetylglucosamine catabolic process	1	1123.5×	0.007	GNPDA1
forebrain regionalization	1	1123.5×	0.007	PGAP1
positive regulation of ER to Golgi vesicle-mediated transport	1	1123.5×	0.007	PGAP1
negative regulation of glycolytic process through fructose-6-phosphate	1	936.2×	0.007	GPI
N-acetylneuraminate catabolic process	1	802.5×	0.007	GNPDA1
attachment of GPI anchor to protein	1	702.2×	0.007	PGAP1
hemostasis	1	561.7×	0.007	GPI
UDP-N-acetylglucosamine biosynthetic process	1	510.7×	0.007	GNPDA1
erythrocyte homeostasis	1	432.1×	0.007	GPI
glucose 6-phosphate metabolic process	1	432.1×	0.007	GPI
fructose 6-phosphate metabolic process	1	374.5×	0.008	GPI
response to muscle stretch	1	255.3×	0.009	GPI
anterior/posterior axis specification	1	244.2×	0.009	PGAP1
response to immobilization stress	1	244.2×	0.009	GPI
response to cadmium ion	1	244.2×	0.009	GPI
canonical glycolysis	1	234.1×	0.009	GPI
embryonic pattern specification	1	181.2×	0.010	PGAP1
mesoderm formation	1	165.2×	0.010	GPI
GPI anchor biosynthetic process	1	165.2×	0.010	PGAP1
response to progesterone	1	165.2×	0.010	GPI
positive regulation of immunoglobulin production	1	160.5×	0.010	GPI
response to testosterone	1	156.0×	0.010	GPI
glycolytic process	1	127.7×	0.012	GPI
generation of precursor metabolites and energy	1	114.6×	0.012	GNPDA1
gluconeogenesis	1	108.0×	0.013	GPI
humoral immune response	1	93.6×	0.014	GPI
positive regulation of endothelial cell migration	1	83.8×	0.015	GPI
learning or memory	1	80.2×	0.015	GPI

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PGAP1	0	0
GNPDA1	0	0
GPI	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GPI	2	Binding:2
GNPDA1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GNPDA1	3.5.99.6	glucosamine-6-phosphate deaminase
GPI	5.3.1.9	glucose-6-phosphate isomerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	GNPDA1, GPI
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PGAP1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PGAP1	0	—
GNPDA1	1	—
GPI	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.